Abstract An epidemic of chronic kidney disease of unknown causes (CKDu) is occurring in laborers who undertake physical work outdoors in hot conditions. The prevalence of CKDu is predicted to escalate due to increasing temperatures and improved diagnostics. Workers in the U.S. are at risk of CKDu. There are ~15 million Americans who work in outdoor occupations and are often exposed to heat. It is estimated that ~15% of workers in endemic areas will develop CKDu. By extension, there are at least 2.3 million American workers at risk of developing CKDu. The prevailing hypothesis underlying the cause of CKDu is that heat strain (i.e., increases in core body temperature) and dehydration elicited by physical work in the heat brings about acute kidney injury (AKI), and with repeated insults leads to CKDu. Notably, the incidence and severity of AKI predicts the subsequent development of chronic kidney disease. Thus, to protect American workers against CKDu there is a need to determine if the heat strain and dehydration exposures encountered by workers are capable of eliciting AKI. The NIOSH heat stress and hydration recommendations aim to minimize heat strain and dehydration. However, they were not developed with regards for renal health. Therefore, the overall objective of this research is to determine if the NIOSH heat stress and hydration recommendations protect workers from AKI. Specific Aim 1 will systematically determine if the NIOSH heat stress recommendations protect workers from AKI. Moreover, Specific Aim 2 will examine if the NIOSH hydration recommendations protect workers from AKI when undertaking physical work in the heat. Finally, Specific Aim 3 will elucidate if the type of rehydration beverage modulates the severity of AKI induced by physical work in the heat. There is concern and debate in the hydration recommendations regarding electrolyte prescription and the consumption of energy drinks in heat stressed workplaces. This Specific Aim will directly inform these concerns. These Specific Aims will study a racially/ethnically diverse cohort of adults in proportions that are congruent with those populations who work in outdoor industries regularly exposed to heat. These participants will undertake simulated physical work in laboratory-based studies under conditions that are representative of those encountered in industries regularly expose to heat stress. The information gained from this project will be disseminated in a timely manner and will inform end users and policy makers. Thus, the intermediate outcome of our project is the translation of the obtained knowledge into the NIOSH heat stress and hydration recommendations, embracing the NIOSH Research to Practice Initiative. This project also addresses a number of National Occupational Research Agenda sector program items aimed at elucidating and mitigating the health impacts of heat stress and strain in the workplace. Finally, the obtained information will serve as a critical benchmark for subsequent studies aiming to identify and examine strategies to mitigate the risk of AKI and CKDu in workers who undertake physical work in hot conditions.